This Program Project application focus on characterizing the cellular, biochemical, and functional mechanisms by which the renin-angiotensin system (RAS) participates in the control of cardiovascular function and the pathogenesis of arterial hypertension. The broad objective of proposed studies is to explore the biochemical, anatomical, and physiological substrate for the neural actions of angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(1-7)] on the neuronal circuits of the brain involved in the regulation of blood pressure and renal function. The studies will be done in a novel model of high blood pressure produced by the insertion of the mouse Ren-2 gene [(mRen2)-27] into the rat genome. We will characterize the mechanism(s) by which Ang peptides function in the brain of transgenic (TG) hypertensive rats by studying: 1) the expression and regulation of Ang peptides and Ang-forming enzymes (Project 1); 2) the distribution, axonal transport mechanism, and function of brain Ang receptors (Project 2); and 3) the ability of ANg peptides to stimulate selective changes on second messengers in both neural and vascular cell (Project 3). The significance of tissue angiotensin systems in the control of blood pressure and the pathogenesis of TG hypertension will be assessed by: 1) studying the actions of brain Ang peptides in the control of vasopressin (Project 4); and 2) evaluating the role of angiotensinergic pathways in the control of sympathetic outflow (Project 5). The expression of a strong sexual dimorphism for blood pressure in TG rats provides the opportunity to determine the mechanisms by which estrogen acts on the RAS to modulate vascular tone and reactivity (Project 6). Research strategies will utilize the professional expertise and equipment described in three of four proposed specialized resource units (Core B, Neuroanatomy; Core C, Biochemistry; and Core D, Molecular Genetics). Biostatistics support and scientific management will be coordinated through Core A, Administration and Biostatistics. Transgenic hypertensive rats and negative littermates will be provided from founder breeder [mRen-2d)27] established in our program. From studies done to-date, our research suggest that investigation of this model of hypertension will allow for the first time a fundamental analysis of the function of the brain and peripheral angiotensin system in the pathogenesis of high blood pressure. The investigation of this problem will uncover novel approaches to the treatment of hypertensive vascular disease.